Process for the manufacture of herbicidal 1-{[2-(cyclopropylcarbonyl)phyenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)urea compounds

ABSTRACT

There is provided an effective and efficient, three step process for the manufacture of crop-selective, herbicidal 1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)urea compounds, and an intermediate for use therein.

BACKGROUND OF THE INVENTION

1-{[2-(Cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)ureacompounds which are useful as crop-selective herbicidal agents aredisclosed in U.S. Pat. Nos. 5,009,699 and 5,280,007. In particular,1-{[o-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)ureais being developed as a herbicide for control of a wide range of dicotand sedge weed species infesting cereals and rice. Additionally,1-{[o-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)ureabinds tightly to soil and would not be expected to pose a threat togroundwater by leaching from soil. Further,1-{[o-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)ureahas been shown to be very safe for mammals and other non-targetorganisms.

Since 1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)urea compounds are highly active, crop-selectiveherbicidal agents and are environmentally benign, there is ongoingresearch to discover and develop effective and efficient processes fortheir manufacture.

U.S. Pat. No. 4,401,816 discloses sulfamoyl chlorides which are usefulin the preparation of sulfamides and pyrrole sulfonamides. However, thatpatent does not disclose a process for the preparation of sulfamoyl ureacompounds.

U.S. Pat. No. 3,939,158 discloses N-(2,4-dihalo-s-triazin-6-yl)ureas anda process for their manufacture. However, the patentee does not describea process for the preparation of sulfamoyl urea compounds.

It is therefore an object of the present invention to provide aneffective and efficient process for the manufacture of1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)ureacompounds.

It is also an object of the present invention to provide intermediatecompounds which are useful in the process of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to an effective and efficient, three stepprocess for the manufacture of a1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)ureahaving the structural formula I ##STR1## wherein Y is hydrogen, halogen,C₁ -C₄ alkyl or C₁ -C₄ haloalkyl; and

R is C₁ -C₆ alkyl, which comprises reacting a2-amino-4,6-dihalopyrimidine having the structural formula II ##STR2##where X and X₁ are each independently Cl, Br or I with chlorosulfonylisocyanate in the presence of a first solvent to obtain an intermediatecompound, reacting the intermediate compound in situ with a2-aminophenyl cyclopropyl ketone having the structural formula III##STR3## wherein Y is as described above and a base to form a1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureahaving the structural formula IV ##STR4## wherein Y, X and X₁ are asdescribed above, and reacting the formula IV urea with at least abouttwo molar equivalents of an alkali metal alkoxide having the structuralformula V

    RO.sup.- M.sup.+                                           (V)

wherein M is an alkali metal and R is as described above in the presenceof a second solvent to form the desired formula I compound.

The present invention also relates to1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureashaving the structural formula IV ##STR5## wherein Y is hydrogen,halogen, C₁ -C₄ alkyl or C₁ -C₄ haloalkyl; and

X and X₁ are each independently Cl, Br or I. The formula IV compoundsare useful as intermediate compounds in the manufacture of thecrop-selective1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)ureaherbicidal agents.

DETAILED DESCRIPTION OF THE INVENTION

Weeds cause tremendous global economic losses by reducing crop yieldsand lowering crop quality. In the United States alone, agronomic cropsmust compete with hundreds of weed species. Advantageously, it hasrecently been discovered that1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)ureasare highly active herbicidal agents. Those compounds, especially1-{[o-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)urea,are particularly useful for the selective control of weeds in thepresence of crops.

Advantageously, it has now been found that the crop-selective herbicidalagents of formula I may be obtained in high yield and good purity by theeffective and efficient, three step process of the present invention.

One of the preferred embodiments of the present invention involvesreacting a formula II 2-amino-4,6-dihalopyrimidine as described abovewith at least about one molar equivalent of chlorosulfonyl isocyanate inthe presence of a first solvent preferably at a temperature range ofabout -20° C. to 10° C., more preferably about -5° C. to 5° C., to forman intermediate compound, reacting the intermediate compound in situwith at least about one molar equivalent of a formula III 2-aminophenylcyclopropyl ketone as described above and at least about one molarequivalent, preferably about one to three molar equivalents of a base ata temperature range of about -20° C. to 30° C., more preferably about-5° C. to 15° C. to form a formula IV1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureaas described above, and reacting the formula IV urea with at least abouttwo molar equivalents, preferably about two to four molar equivalents ofa formula V alkali metal alkoxide as described above in the presence ofa second solvent preferably at a temperature range of about 20° C. to100° C., more preferably about 40° C. to 80° C., to form a1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dialkoxy-2-pyrimidinyl)ureaof formula I.

The product formula I compounds may be isolated by conventionaltechniques such as acidification and dilution of the reaction mixturewith water followed by filtration of the formula I product or extractionof the product with a suitable solvent.

The process of the present invention is especially useful for thepreparation of1-{[o-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)urea; and1-{[2-(cyclopropylcarbonyl)-4-fluorophenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)urea.

Surprisingly, it has been found that1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureacompounds of formula IV are important intermediates in the manufactureof the crop-selective herbicidal agents of formula I. Formula IVcompounds which are particularly suitable for use in the process of thepresent invention include1-{[o-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dichloro-2-pyrimidinyl)urea;and1-{[2-(cyclopropylcarbonyl)-4-fluorophenyl]sulfamoyl}-3-(4,6-dichloro-2-pyrimidinyl)urea,among others.

Alkali metals which are suitable for use in the process of the presentinvention include sodium, potassium and lithium with sodium andpotassium being preferred. Bases suitable for use in the inventionprocess include organic bases such as tri(C₁ -C₄ alkyl)amines, pyridine,substituted pyridines, quinoline, substituted quinolines, and the likewith tri(C₁ -C₄ alkyl)amines such as triethylamine being preferred.

First solvents suitable for use in the above process include inert,nonprotic solvents such as halogenated aliphatic hydrocarbons such asmethylene chloride and ethylene dichloride, aromatic hydrocarbons suchas toluene, ethers such as ethyl ether and tetrahydrofuran, and the likewith halogenated aliphatic hydrocarbons such as methylene chloride andethylene dichloride being preferred. Second solvents suitable for use inthe process of the present invention include tetrahydrofuran,N,N-dimethylformamide, dioxane, ROH alcohols wherein R corresponds tothe R group described above for formula V, and the like with ROHalcohols such as methanol being preferred.

In order to facilitate a further understanding of the invention, thefollowing examples are presented to illustrate more specific detailsthereof. The invention is not to be limited thereby except as defined inthe claims.

EXAMPLE 1 Preparation of1-{[o-(Cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dichloro-2-pyrimidinyl)urea##STR6##

2-Amino-4,6-dichloropyrimidine (6.15 g, 0.0375 mol) is added portionwiseto a solution of chlorosulfonyl isocyanate (5.30 g, 0.0375 mol) inmethylene chloride at 0° C. The resulting mixture is stirred at 0° to 2°C. for two hours and a solution of o-aminophenyl cyclopropyl ketone(6.04 g, 0.0375 mol) and triethylamine (3.8 g, 0.0406 mol) in methylenechloride is slowly added to the mixture. The resulting solution isstirred at room temperature overnight, washed with water, dried overanhydrous magnesium sulfate and concentrated in vacuo to obtain thetitle product as a yellow solid (14.3 g, 75% real by HPLC analysis, 68%yield) which is used as a starting material for Example 2 withoutpurification. A portion of the yellow solid is purified to yield thetitle product, mp 114°-116° C.

EXAMPLE 2 Preparation of1-{[o-(Cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dimethoxy-2-pyrimidinyl)urea##STR7##

A mixture of sodium methoxide (1.08 g, 0.02 mol) in methanol is addedslowly to a mixture of1-{[o-(cyclopropyl)phenyl]sulfamoyl}-3-(4,6-dichloro-2-pyrimidinyl)ureafrom Example 1 (4.30 g, 0.01 mol) in methanol at 60° C. The reactionmixture is heated at 60° C. for two hours, cooled, treated withadditional sodium methoxide (0.54 g), refluxed overnight, cooled,acidified and concentrated in vacuo to obtain a residue. The residue isslurried in methanol, filtered, washed sequentially with methanol andwater, and dried in a vacuum oven at 55°-60° C. to give the titleproduct as a cream colored solid (2.2 g, 98.6% real by HPLC analysis,70% yield, mp 168.5°-169.5° C.).

I claim:
 1. A process for the preparation of a compound having thestructural formula ##STR8## wherein Y is hydrogen, halogen, C₁ -C₄ alkylor C₁ -C₄ haloalkyl; andR is C₁ -C₆ alkyl, which comprises reacting a2-amino-4,6-dihalopyrimidine having the structural formula ##STR9##wherein X and X₁ are each independently Cl, Br or I with chlorosulfonylisocyanate in the presence of a first solvent to obtain an intermediatecompound, reacting the intermediate compound in situ with a2-aminophenyl cyclopropyl ketone having the structural formula ##STR10##wherein Y is as described above and a base to form a1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureahaving the structural formula ##STR11## wherein Y, X and X₁ are asdescribed above, and reacting the1-{[2-(cyclopropylcarbonyl)phenyl]sulfamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureawith at least about two molar equivalents of an alkali metal alkoxidehaving the structual formula

    RO.sup.- M.sup.+

wherein M is an alkali metal and R is as described above in the presenceof a second solvent to form the desired compound.
 2. The processaccording to claim 1 wherein the first solvent is selected from thegroup consisting of a halogenated aromatic hydrocarbon, an aromatichydrocarbon and an ether, and the second solvent is selected from thegroup consisting of an ROH alcohol, tetrahydrofuran,N,N-dimethylformamide and dioxane.
 3. The process according to claim 2wherein the first solvent is selected from the group consisting ofmethylene chloride and ethylene dichloride, and the second solvent is aROH alcohol.
 4. The process according to claim 1 whereinY is hydrogen orF; R is methyl; and M is sodium or potassium.
 5. The process accordingto claim 4 whereinY is hydrogen; and X and X₁ are Cl.
 6. The processaccording to claim 4 whereinY is F; and X and X₁ are Cl.
 7. The processaccording to claim 1 wherein the 2-amino-4,6-dihalopyrimidine is reactedwith the chlorosulfonyl isocyanate at a first temperature of about -20°C. to 10° C., the intermediate compound is reacted with the2-aminophenyl cyclopropyl ketone and the base at a second temperature ofabout -20° C. to 30° C., and the1-{[2-(cyclopropylcarbonyl)phenyl]sufamoyl}-3-(4,6-dihalo-2-pyrimidinyl)ureais reacted with the alkali metal alkoxide at a third temperature ofabout 20° C. to 100° C.
 8. The process according to claim 7 wherein thefirst temperature is about -5° C. to 5° C., the second temperature isabout -5° C. to 15° C., and the third temperature is about 40° C. to 80°C.
 9. The process according to claim 1 wherein the base is selected fromthe group consisting of a tri(C₁ -C₄ alkyl)amine, pyridine andquinoline.
 10. The process according to claim 9 wherein the base is atri(C₁ -C₄ alkyl)amine.
 11. The process according to claim 10 whereinthe tri(C₁ -C₄ alkyl)amine is triethylamine.